The primary objective of this proposal is to develop pharmacological agents that inhibit neuronal programmed cell death (apoptosis). Techniques in molecular biology will be combined with animal models of cerebral ischemia to characterize the molecular mechanisms underlying neuronal apoptosis, and to evaluate the effects of potential therapeutic agents. Based on recent findings that neuronal apoptosis is triggered by ischemia/anoxia, it is likely that pharmacological agents that modulate apoptosis will be useful in the treatment of a number of clinically relevant ischemic indications. These include stroke, cardiac arrest, and head and spinal trauma, all of which constitute commercially significantly therapeutic markets worldwide. The objective in Phase I is to demonstrate both in vitro and in vivo that genes known to regulate apoptosis in other cell types are involved in regulating neuronal apoptosis. The expression of these genes (e.g. ICE, bcl-2, and bax) will be monitored following ischemia both in vitro and in vivo. Antisense oligonucleotides against these genes will be tested for their ability to provide neuroprotection. The objective of Phase II will be to evaluate the use of antisense oligonucleotides against apoptosis genes as potential therapeutic agents, and to screen for small molecule inhibitors of apoptosis. PROPOSED COMMERCIAL APPLICATION: The research should provide therapeutic agents useful in the treatment of ischemia-induced brain injury (global ischemia due to cardiac arrest, stroke).